Methods for concomitant administration of colchicine and macrolide antibiotics

ABSTRACT

Methods for concomitant administration of colchicine together with one or more macrolide antibiotics, e.g., clarithromycin, are disclosed. Such methods reduce the dangers commonly associated with such concomitant administration and provide additional benefits.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/576,355 filed Oct. 9, 2009, which is a continuation-in-part of U.S.patent application Ser. No. 12/327,258 filed on Dec. 3, 2008, now U.S.Pat. No. 7,619,004, issued Nov. 17, 2009, and a continuation of part ofU.S. application Ser. No. 12/368,700 filed on Feb. 10, 2009, now U.S.Pat. No. 7,601,758, issued Oct. 13, 2009, all of which claim the benefitof Provisional Patent Application Ser. No. 61/190,053, filed Oct. 15,2008, and all of which are incorporated herein in their entirety.

BACKGROUND

This application relates to methods allowing for the co-administrationof colchicine together with one or more macrolide antibiotics fortherapeutic purposes with less danger than is associated with priormethods of administration.

Colchicine:

Colchicine, chemical name(−)-N-[(7S,12aS)-1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]-acetamide,is a pale yellow powder soluble in water in 1:25 dilution.

Colchicine is an alkaloid found in extracts of Colchicum autumnale,Gloriosa superba, and other plants. Among its many biologicalactivities, colchicine blocks microtubule polymerization and arrestscell division. It has adversely affected spermatogenesis in humans andin some animal species under certain conditions.

Colchicine is a microtubule-disrupting agent used in the treatment ofgout and other conditions that may be treated, relieved or preventedwith anti-inflammatory treatment. Colchicine impairs the motility ofgranulocytes and can prevent the inflammatory phenomena that initiate anattack (or flare) of gout. Colchicine also inhibits mitosis, thusaffecting cells with high turnover such as those in the gastrointestinaltract and bone marrow; therefore, the primary adverse side effectsinclude gastrointestinal upset such as diarrhea and nausea. More seriousside effects include morbid complications such as myopathy, neuropathy,bone marrow suppression and drug-induced cytopenia. Particularexpressions of these morbid complications may include neuromusculartoxicity with paresthesias, pancytopenia, and seizures.

Colchicine has a low therapeutic index. The margin between an effectivedose and a toxic dose of colchicine is much narrower than that of mostother widely used drugs. Consequently, actions that result in increasedcolchicine levels in patients receiving colchicine therapy areparticularly dangerous. Co-administration of colchicine to patientsalong with certain other drugs can have the effect of increasingcolchicine levels. Such drug-drug interactions with colchicine have beenreported to result in serious morbid complications and, in some cases,death.

Colchicine is rapidly absorbed from the gastrointestinal tract. Peakconcentrations occur in 0.5 to 2 hours. The drug and its metabolites aredistributed in leukocytes, kidneys, liver, spleen and the intestinaltract. Colchicine is metabolized in the liver and excreted primarily inthe feces with 10 to 20% eliminated unchanged in the urine.

Gout:

Gout (or gouty arthritis) is a disease caused by a build up of uricacid. Such a build up is typically due to an overproduction of uric acidor to a reduced ability of the kidney to excrete uric acid. Gout is morecommon in certain groups of patients, including adult males,postmenopausal women, and hypertensives. Heavy alcohol use, diabetes,obesity, sickle cell anemia, and kidney disease also increase the riskof developing gout. The condition may also develop in people who takedrugs that interfere with uric acid excretion.

In gout, crystals of monosodium urate (a salt of uric acid) aredeposited in joints, e.g., on articular cartilage, as well as in and ontendons and surrounding tissues. These deposits correlate with elevatedconcentrations of uric acid in the blood stream and are believed toprovoke the painful inflammatory reaction that occurs in affectedtissues. Gout is characterized by excruciating, sudden, unexpected,burning pain, as well as by swelling, redness, warmness, and stiffnessin the affected joint. Low-grade fever may also be present. The patientusually suffers from two sources of pain. The patient experiencesintense pain whenever an affected joint is flexed. The inflammation ofthe tissues around the joint also causes the skin to be swollen, tenderand sore if it is even slightly touched. For example, a blanket or eventhe lightest sheet draping over the affected area could cause extremepain.

A gout flare is a sudden attack of pain in affected joints, especiallyin the lower extremities, and most commonly in the big toe. In afflictedindividuals, the frequency of gout flares typically increases over time.In this fashion, gout progresses from acute gout to chronic gout, whichinvolves repeated episodes of joint pain.

In acute gout flares, symptoms develop suddenly and usually involve onlyone or a few joints. The big toe, knee, or ankle joints are most oftenaffected. The pain frequently starts during the night and is oftendescribed as throbbing, crushing, or excruciating. The joint appearsinfected, with signs of warmth, redness, and tenderness. Gout flaresappear substantially more frequently with more intensive urate-loweringregimens and are a common consequence of therapy with allopurinol. Tworandomized clinical trials assessed the efficacy of colchicine 0.6 mgtwice a day for the prophylaxis of gout flares in patients with goutinitiating treatment with urate lowering therapy. In both trials,treatment with colchicine decreased the frequency of gout flares. Flaresof painful joints may go away in several days, but may return from timeto time. Subsequent flares usually last longer. Acute gout may progressto chronic gout flares, or may resolve without further attacks.

The chronic appearance of several attacks of gout yearly can lead tojoint deformity and limited joint motion. Nodular uric acid deposits,called tophi, may eventually develop in cartilage tissue, tendons, andsoft tissues. These tophi are a hallmark of chronic gout, which usuallydevelop only after a patient has suffered from the disease for manyyears. Deposits of monosodium urate can also occur in the kidneys ofgout sufferers, potentially leading to chronic kidney failure.

Use of Colchicine to Treat Gout:

Colchicine can reduce pain in attacks of acute gout flares and also canbe used beneficially for treating adults for prophylaxis of gout flares.Although its exact mode of action in the relief of gout is notcompletely understood, colchicine is known to decrease the inflammatoryresponse to urate crystal deposition by inhibiting migration ofleukocytes, to interfere with urate deposition by decreasing lactic acidproduction by leukocytes, to interfere with kinin formation and todiminish phagocytosis and subsequent inflammatory responses.

The anti-inflammatory effect of colchicine is relatively selective forgouty arthritis. However, other types of arthritis occasionally respond.It is neither an analgesic nor a uricosuric and will not preventprogression of acute gout to chronic gout. It does have a prophylactic,suppressive effect that helps to reduce the incidence of acute attacksas well as to relieve the residual pain and mild discomfort thatpatients with gout occasionally experience between attacks.

Macrolide Antibiotics:

Macrolide compounds are natural products and natural product derivativescharacterized by the presence of a macrocyclic (large) lactone ringknown as a macrolide ring. The macrolide antibiotics are importanttherapeutic agents. Commercially available macrolide antibiotics includeazithromycin, clarithromycin, dirithromycin, erythromycin, androxithromycin.

Clarithromycin is a semi-synthetic macrolide antibiotic with in vitroactivity against a variety of aerobic and anaerobic gram-positive andgram-negative microorganisms, as well as most Mycobacterium aviumcomplex (MAC) microorganisms. The drug is believed to exert itsantibacterial action by binding to 50S ribosomal subunits in susceptiblemicroorganisms, resulting in inhibition of protein synthesis.

Clarithromycin is indicated in the treatment of mild to moderateinfections in adults and children caused by susceptible strains ofmicroorganisms, such as Legionella pneumophila. Haemophilus influenzae,Streptococcus pneumoniae and Neisseria gonorrhoeae. Clarithromycin isalso used to treat pharyngitis (tonsillitis), sinusitis, bronchitis,community-acquired pneumonia, uncomplicated skin infections, anddisseminated mycobacterial infections. The usual adult dose is 250 or500 mg every 12 hours (500 or 100 mg per day) for 7 to 14 days, takenwithout regard to food.

Clarithromycin is rapidly absorbed from the gastrointestinal tractfollowing oral administration, with an absolute bioavailability ofapproximately 50%. Peak plasma concentrations with single doses arereached within 2 to 3 hours and steady-state plasma concentrations arereached within 3 to 4 days. Food slightly delays the onset of absorptionand time to peak concentration and increases the peak concentration byabout 24%, but does not affect the extent of exposure. Clarithromycindistributes readily into body tissues and fluids and is not highly boundto plasma proteins (65 to 75%).

Cytochrome p450 (CYP) Enzymes:

CYP enzymes are agents of drug metabolism that are found in the liver,the gastrointestinal tract and other locations in the body. CYP enzymesoccur in a variety of closely related proteins referred to as isozymes.Some of these that have been identified as important in drug metabolismare CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1,CYP3A4, and CYP3A5. Different CYP isozymes may preferentially metabolizedifferent drugs. For example, phenytoin and fosphenytoin have beenreported to be preferentially metabolized by CYP2C9, CYP2C19, andCYP3A4, while CYP2D6 has been reported to be responsible for themetabolism of many psychotherapeutic agents, such as thioridazine.

CYP Isozymes and Drug-Drug Interactions:

Examples of CYP-mediated drug-drug interactions include those involvingCYP1A2 and CYP2E1 isozymes, which have been reported to be involved indrug-drug interactions involving theophylline, and those involvingCYP2C9, CYP1A2, and CYP2C19, which have been reported to be involved indrug-drug interactions involving warfarin.

The 3A family of CYP isozymes, particularly CYP3A4, is also known to beinvolved in many clinically significant drug-drug interactions,including those involving colchicine and macrolide antibiotics, as wellas those involving non-sedating antihistamines and cisapride. CYP3A5shares very similar protein structure, function and substratespecificity with CYP3A4. The CYP3A5*3 allele is a gene variant that doesnot express CYP3A5 enzyme. As a result of this genetic variation, abouthalf of African-American subjects and 70-90% of Caucasian subjects donot express CYP3A5, while expression is more common in other ethnicgroups.

While drugs are often targets of CYP-mediated metabolism, some may alsoalter the expression and activity of such enzymes, thus impacting themetabolism of other drugs.

Colchicine is both a target of and a modulator of CYP isozymes. Thebiotransformation of colchicine in human liver microsomes involvesformation of 3-demethylchochicine and 2-demethylcolchicine. As shown byexperiments using antibodies against CYP3A4 and experiments usingchemical inhibition of CYP3A4, this transformation is correlated with(and thus apparently mediated by) CYP3A4 activity. CYP2A6, CYP2C9,CYP2C19, CYP2D6, and CYP2E1 do not appear to catalyze thisbiotransformation.

Studies on the effect of colchicine on expression of selected CYPisozymes in primary cultures of human hepatocytes have been reported.Dvorak et al. (Acta Univ. Palacki. Olomuc., Fac. Med. (2000) 143:47-50)provided preliminary data on the effect of colchicine and several of itsderivatives on protein levels of CYP1A2, CYP2A6, CYP2C9/19, CYP2E1, andCYP3A4 as assessed by immunoblotting. Colchicine caused an increase inCYP2E1 protein levels and appeared to decrease protein levels of CYP1A2,CYP2C9/19, and CYP3A4, with 10 μM colchicine causing a greater reductionin each isozyme than 1 μM colchicine. The 3-demethylchochicinemetabolite was reported to cause a decrease in protein for CYP1A2,CYP2C9/19, CYP2E1, and CYP3A4. The levels of CYP2A6 appeared unaffectedby colchicine or any of the tested metabolites. In a more completereport on expression of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2E1, andCYP3A4, Dvorak et al. (Toxicology in Vitro (2002) 16:219-227) concludedthat CYP1A2 protein content in 1 μM colchicine treated cells was notdifferent from that in control cells, while the inducer TCDD increasedthe level of CYP1A2 protein by an average of three-fold. The levels ofCYP2A6 protein were apparently unaffected by colchicine, while enzymeactivities of CYP3A4 and CYP2C9 were significantly decreased bycolchicine and activity of CYP2E1 was not affected. Northern blotsshowed that colchicine suppressed CYP2C9 mRNA levels by about 20% anddid not alter CYP3A4 mRNA levels as compared to control cells. Asubsequent study by Dvorak et al. (Mol. Pharmacol. (2003) 64:160-169)showed that colchicine decreased both basal and rifampicin-inducible andphenobarbital-inducible expression of CYP2B6, CYP2C8/9, and CYP3A4.

Like colchicine, clarithromycin is a target of metabolism by CYP3Aisozymes. In non-fasting healthy human subjects, the eliminationhalf-life of clarithromycin is about 3 to 4 hours with 250 mgadministered every 12 hours, but increases to 5 to 7 hours with 500 mgadministered every 8 to 12 hours. Approximately 20% and 30% of the dose,respectively, is excreted as unchanged drug in urine following oraladministration of 250 and 500 mg clarithromycin given every 12 hours.Approximately 10 to 15% of the dose is excreted in urine as14-hydroxyclarithromycin, an active metabolite of clarithromycin withsubstantial antibacterial activity. About 40% of an oral clarithromycindose is excreted in feces.

Clarithromycin is also a potent inhibitor of CYP3A isozymes, as areother macrolide antibiotics. This inhibition is not rapidly reversible.Due to the limited reversibility of the inhibition of CYP3A isozymes byclarithromycin, CYP3A activity may not return to normal after a courseof treatment with clarithromycin until the body produces adequateamounts of CYP3A isozymes to replace those irreversibly inhibited by theclarithromycin. Thus, it may take one to two weeks for CYP3A metabolicactivity to return to normal following treatment with clarithromycin orother macrolide antibiotics.

P-glycoprotein (Pgp) is an ATP-dependent cell surface transportermolecule. Pgp actively pumps certain compounds, notably including drugssuch as colchicine, out of cells. Pgp is encoded by the Adenosinetriphosphate-binding cassette subfamily B member 1 (ABCB 1) gene, alsoreferred to as the multiple drug resistance 1 gene (MDR1).

Clarithromycin is an inhibitor of Pgp, as are other macrolideantibiotics. In vitro, agents that inhibit CYP 3A4 typically alsoinhibit Pgp, and the magnitude of Pgp inhibition in vitro generallytrends proportionally with magnitude of CYP 3A4 inhibition. However,equipotent CYP 3A4 inhibitors can exhibit different degrees of Pgpinhibition.

Thus clarithromycin and other macrolide antibiotics, in addition toinhibiting the metabolic breakdown of colchicine by inhibiting CYP 3A4isozymes, can block a mechanism by which colchicine is pumped out ofcells. Both the inhibition of colchicine breakdown by CYP 3A4 and theinhibition of the pumping of colchicine out of cells by Pgp have theeffect of increasing the intracellular levels of colchicine.

Since colchicine acts intracellularly, the combined effects of CYP 3A4inhibition and Pgp inhibition by clarithromycin (and related macrolideantibiotics) can cause colchicine toxicity in patients taking what wouldbe a safe dose of colchicine in the absence of concomitant macrolideantibiotic administration.

Drug-drug interactions, such as the enhancement of colchicine toxicityby macrolide antibiotics, present a health risk to patients and amedical challenge for all medical care workers. Various studies ofadverse reactions from exposure to multiple drugs have found that6.5-23% of the adverse reactions result from drug-drug interactions.Unfortunately, each year a number of deaths occur as the direct resultof patients adding a concomitant prescription pharmaceutical product totheir existing medication regimen.

With regard to co-administration of colchicine with clarithromycin andother macrolide antibiotics, warnings have recently been publishedurging caution, or arguing that the two drugs should not beco-administered. For example, on Jul. 5, 2006 the US Food and DrugAdministration (the FDA) approved safety labeling changes forclarithromycin tablets, extended-release tablets, and oral suspension towarn of the risk for increased exposure to colchicine in patientsreceiving both drugs. The Warnings section of the prescribinginformation for clarithromycin now includes the following statement:“There have been post-marketing reports of colchicine toxicity withconcomitant use of clarithromycin and colchicine, especially in theelderly, some of which occurred in patients with renal insufficiency.Deaths have been reported in some such patients.” In addition, thefollowing was added to the Precautions section of the prescribinginformation: “[c]olchicine is a substrate for both CYP3A and the effluxtransporter, P-glycoprotein (Pgp). Clarithromycin and other macrolidesare known to inhibit CYP3A and Pgp. When clarithromycin and colchicineare administered together, inhibition of Pgp and/or CYP3A byclarithromycin may lead to increased exposure to colchicine. Patientsshould be monitored for clinical symptoms of colchicine toxicity.”

A 2006 report entitled “Life-threatening Colchicine Drug Interactions”cautioned that “[c]olchicine should not be used with clarithromycin orerythromycin, and given the potential for fatal outcomes, it would beprudent to avoid all PGP inhibitors with colchicine” (Horn, J. R. andHansten, P. D., Pharmacy Times, May 2006, p. 111).

More recently, a publication in May, 2008 ended with the conclusion that“[t]he combined prescription of clarithromycin or other CYP3A4inhibitors and colchicine should be avoided.” Van der Velden, et al.,(Neth. J. Med. 2008 May; 66(5):204-6).

There accordingly remains a need in the art for improved methods foradministering colchicine to patients who are concomitantly being treatedwith macrolide antibiotics so as to reduce the occurrence of dangerouscolchicine toxicity. The present disclosure addresses this need andprovides further advantages.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows mean colchicine plasma concentrations followingadministration of single and multiple oral doses of colchicine 0.6 mg inhealthy adults, N=13, Y axis=colchicine concentration, ng/mL, Xaxis=time in hours, ♦=day 1, □=day 25. See Example 1.

FIG. 2 shows a pharmacokinetic profile comparison of single-dosecolchicine (0.6 mg, alone) and single-dose colchicine (0.6 mg)co-administered with steady-state clarithromycin in healthy adults, Yaxis=colchicine concentration, ng/mL, X axis=time in hours, N=23, ◯=day1, ♦=day 29. See Example 2.

SUMMARY

Disclosed herein are methods for more safely administering colchicineconcomitantly with administration of macrolide antibiotics such asclarithromycin or erythromycin. It has now been discovered that certainreduced or limited colchicine dosages, when administered withconcomitantly administered recommended dosage amounts of macrolideantibiotics, certain “colchicine plus macrolide” dosing regimens,achieve plasma colchicine levels that are therapeutically effective, butare not significantly higher, and therefore not significantly moretoxic, than plasma levels achieved by administration of manufacturers'recommended colchicine dosage amounts in the absence of concomitantmacrolide antibiotic administration. Thus, in spite of recent publishedwarnings that the two should not be concomitantly administered,colchicine and macrolide antibiotics can be administered concomitantlywithout undue hazard when colchicine is administered as disclosedherein.

In one embodiment, colchicine treatment is administered to a patient insuffering from a condition treatable with colchicine, and the patient isconcomitantly receiving administration of a macrolide antibiotic totreat an infection. The colchicine therapy may involve either palliativeor prophylactic treatment, or both.

In one embodiment, colchicine is employed in the prophylaxis of goutflares in a human individual, that is, to prevent gout flares. Suchtreatment can also be referred to as chronic treatment, meaninglong-term treatment to reduce the occurrence of gout flares. In oneembodiment, the method comprises determining a first colchicine dosageamount adapted for daily oral administration to the gout patient toprevent gout flares in the absence of concomitant administration ofclarithromycin or erythromycin, determining a second colchicine dosageamount that is a 50% to 75% reduction of the first colchicine dosageamount, and orally administering the second colchicine dosage amount tothe gout patient who is concomitantly receiving administration ofclarithromycin or erythromycin. The second colchicine dosage amount isadministered to the patient in one or more doses one or more times perday every day, or double the second colchicine dosage amount isadministered to the patient in one or more doses per day every otherday.

In certain embodiments, in this method, the 50% to 75% reductioncomprises one or more of 1) reducing the number of doses of colchicineadministered per day, 2) reducing the amount of colchicine administeredper dose, and 3) reducing the administration of colchicine fromadministration every day to administration every other day. For example,in this method, the 50% to 75% reduction may comprise reducing both thenumber of doses of colchicine administered per day and the amount ofcolchicine administered per dose.

In other aspects of these embodiments, one or more (where not mutuallyexclusive) of the following applies: 1) the patient is administered eachdose of colchicine as one 0.6 mg colchicine tablet or as one half of a0.6 mg colchicine tablet, 2) the patient is an adult, 3) the adultpatient is less than 70 years old, 4) the patient is receivingconcomitant administration of clarithromycin, 6) the second colchicinedosage amount is a one-half reduction of the first colchicine dosageamount, 7) the second colchicine dosage amount is a two-thirds reductionof the first colchicine dosage amount, 8) the second colchicine dosageamount is a three-quarters reduction of the first colchicine dosageamount, 9) the first colchicine dosage amount is about 1.2 mg per dayand the second colchicine dosage amount is about 0.3 mg per day, 10) thefirst colchicine dosage amount is about 0.6 mg per day and the secondcolchicine dosage amount is about 0.15 mg per day.

In aspects of these embodiments, the second colchicine dosage amount ofabout 0.3 mg per day is administered as one half of a 0.6 mg colchicinetablet once a day every day, and the second colchicine dosage amount ofabout 0.15 mg per day is administered as one half of a 0.6 mg colchicinetablet once a day every other day.

In one embodiment, a method of using colchicine for prophylactictreatment of gout flares in a human gout patient so as to reduce theoccurrence of colchicine toxicity when said patient is receivingconcomitant administration of clarithromycin or erythromycin, comprises:orally administering a second colchicine daily dosage amount forprophylactic treatment of gout flares to the human gout patient who isconcomitantly receiving administration of clarithromycin orerythromycin, wherein the second colchicine daily dosage amount is a 50to 75% reduction of a first colchicine daily dosage amount suitable fordaily oral administration for the prophylactic treatment of gout flaresin the absence of concomitant administration of clarithromycin orerythromycin, wherein concomitant administration of clarithromycin orerythromycin is administration within 1 to 2 days of orallyadministering the second colchicine dosage amount, and wherein the firstcolchicine daily dosage amount is 1.2 mg administered as two 0.6 mgdoses per day, or the first colchicine daily dosage amount is 0.6 mg perday.

In another embodiment, a method of using colchicine for prophylactictreatment of gout flares in a human gout patient so as to reduce theoccurrence of colchicine toxicity when said patient is receivingconcomitant administration of clarithromycin or erythromycin, comprises:orally administering a second colchicine daily dosage amount forprophylactic treatment of gout flares to the human gout patient who isconcomitantly receiving administration of clarithromycin orerythromycin, wherein the second colchicine daily dosage amount is a 75%reduction of a first colchicine daily dosage amount suitable for dailyoral administration for the prophylactic treatment of gout flares in theabsence of concomitant administration of clarithromycin or erythromycin,wherein concomitant administration of clarithromycin or erythromycin isadministration within 1 to 2 days of orally administering the secondcolchicine dosage amount. In certain embodiments, the first colchicinedaily dosage amount is 1.2 mg administered as two 0.6 mg doses per day,or the first colchicine daily dosage amount is 0.6 mg per day.

In another embodiment, a method of using colchicine for prophylactictreatment of gout flares in an adult human gout patient so as to reducethe occurrence of colchicine toxicity when said patient is receivingconcomitant administration of clarithromycin or erythromycin comprisesadministering a reduced colchicine daily dosage amount to the patientfor prophylactic treatment of gout flares, wherein the reducedcolchicine daily dosage amount is 50-75% of a manufacturers' recommendedcolchicine daily dosage amount for the prophylactic treatment of goutflares in the absence of concomitant clarithromycin or erythromycinadministration, wherein concomitant administration of clarithromycin orerythromycin is administration within 1 to 2 days of orallyadministering the second colchicine dosage amount. In certainembodiments, the manufacturers' recommended colchicine daily dosageamount for the prophylactic treatment of gout flares in the absence ofconcomitant clarithromycin or erythromycin administration is 1.2 mg/dayor 0.6 mg/day.

In another embodiment, a method of using colchicine for prophylactictreatment of gout flares in an adult human gout patient so as to reducethe occurrence of colchicine toxicity when said patient is receivingconcomitant administration of clarithromycin or erythromycin comprisesadministering a reduced colchicine daily dosage amount to the patientfor prophylactic treatment of gout flares, wherein the reducedcolchicine daily dosage amount is 75% of a manufacturers' recommendedcolchicine daily dosage amount for the prophylactic treatment of goutflares in the absence of concomitant clarithromycin or erythromycinadministration, wherein concomitant administration of clarithromycin orerythromycin is administration within 1 to 2 days of orallyadministering the second colchicine dosage amount.

In one embodiment, the daily colchicine is coadministered with aurate-lowering drug such as febuxostat or allopurinol. Daily dosageamounts of febuxostat are typically 40 mg or 80 mg once daily. Dailydosage amounts of allopurinol are 200 to 300 mg per day for patientswith mild gout and 400 to 600 mg per day for those with moderatelysevere tophaceous gout. The appropriate dosage amount may beadministered in divided doses or as a single equivalent dose with the300 mg tablet. Dosage requirements in excess of 300 mg should beadministered in divided doses. The minimal effective dosage amount is100 to 200 mg daily and the maximal recommended dosage amount is 800 mgdaily. To reduce the possibility of flare-up of acute gouty attacks, itis recommended that the patient start with a low dosage amount ofallopurinol (100 mg daily) and increase at weekly intervals by 100 mguntil a serum uric acid level of 6 mg/dL or less is attained but withoutexceeding the maximal recommended dosage amount.

In yet another embodiment, a method of using colchicine for prophylactictreatment of gout flares in a human gout patient that is also receivingtreatment with urate-lowering therapy so as to reduce the occurrence ofcolchicine toxicity when said patient is receiving concomitantadministration of clarithromycin or erythromycin, comprises: orallyadministering a second colchicine daily dosage amount for prophylactictreatment of gout flares to the human gout patient who is concomitantlyreceiving administration of clarithromycin or erythromycin, wherein thesecond colchicine daily dosage amount is a 75% reduction of a firstcolchicine daily dosage amount suitable for daily oral administrationfor the prophylactic treatment of gout flares in the absence ofconcomitant administration of clarithromycin or erythromycin, whereinconcomitant administration of clarithromycin or erythromycin isadministration within 1 to 2 days of orally administering the secondcolchicine dosage amount. In certain embodiments, the first colchicinedaily dosage amount is 1.2 mg administered as two 0.6 mg doses per day,or the first colchicine daily dosage amount is 0.6 mg per day. Incertain embodiments, the urate lowering therapy is allopurinol orfebuxostat.

In another embodiment, colchicine is used for the treatment of acutegout, that is, treatment of gout flares. In one embodiment, the methodcomprises determining a first colchicine dosage amount adapted for oraladministration to the gout patient to treat gout flares in the absenceof concomitant administration of clarithromycin or erythromycin,determining a second colchicine dosage amount that is a 50% to 75%reduction, preferably a two-thirds or three quarters reduction, of thefirst colchicine dosage amount, and orally administering the secondcolchicine dosage amount to the gout patient who is concomitantlyreceiving administration of clarithromycin or erythromycin. In oneembodiment, the colchicine administration is not repeated for at leastthree days.

In certain embodiments, the 50% to 75% reduction comprises one or moreof 1) reducing the number of doses of colchicine administered (e.g., perday), 2) reducing the amount of colchicine administered per dose (i.e.,reducing the size of at least one colchicine dose), and 3) reducing theadministration of colchicine from administration every day toadministration every other day. For example, in this method, the 50% to75% reduction may comprise reducing both the number of doses ofcolchicine administered per day and the amount of colchicineadministered per dose. In one embodiment, the colchicine administrationis not repeated for at least three days.

In other aspects of these embodiments, one or more (where not mutuallyexclusive) of the following apply: 1) the patient is administered eachdose of colchicine as one 0.6 mg colchicine tablet or as one half of a0.6 mg colchicine tablet (e.g. one half a scored 0.6 mg colchicinetablet), 2) the patient is an adult, 3) the adult patient is less than70 years old, 4) the patient is receiving concomitant administration ofclarithromycin, 5) the second colchicine dosage amount is about aone-half reduction of the first colchicine dosage amount, 6) the secondcolchicine dosage amount is about a two-thirds reduction of the firstcolchicine dosage amount, 7) the second colchicine dosage amount isabout a three-quarters reduction of the first colchicine dosage amount,8) the first colchicine dosage amount is about 1.8 mg per day and thesecond colchicine dosage amount is about 0.6 mg per day, 9) the secondcolchicine dosage amount is a single dose of about 0.6 mg, and afteradministration of the single dose ingestion of colchicine is stoppeduntil a subsequent gout flare occurs, 10) the second colchicine dosageamount is a single dose of about 0.6 mg of colchicine, and afteradministration of the single dose ingestion of colchicine is notrepeated within a 3-day period.

In an additional embodiment, the first colchicine dosage amount is about1.8 mg per day and the second colchicine dosage amount is a single 0.6mg dose, and preferably ingestion of colchicine is not repeated for atleast three days after the single dose is administered.

In another embodiment, a method of using colchicine to treat a goutflare in a human patient who is receiving concomitant administration ofclarithromycin or erythromycin comprises determining a first colchicinedosage amount adapted for oral administration to the patient to treat agout flare in the absence of concomitant administration ofclarithromycin or erythromycin, determining a second colchicine dosageamount that is a 50-75% reduction of the first colchicine dosage amount,and orally administering the second colchicine dosage amount to thepatient who is experiencing a gout flare and is concomitantly receivingadministration of clarithromycin or erythromycin, wherein concomitantadministration of clarithromycin or erythromycin is administrationwithin 1 to 2 days of orally administering the second colchicine dosageamount, and not repeating colchicine administration for at least threedays.

In another embodiment, a method of using colchicine to treat a goutflare in a human patient who is receiving concomitant administration ofclarithromycin or erythromycin comprises determining a first colchicinedosage amount adapted for oral administration to the patient to treat agout flare in the absence of concomitant administration ofclarithromycin or erythromycin, determining a second colchicine dosageamount that is about a two thirds reduction of the first colchicinedosage amount, and orally administering the second colchicine dosageamount to the patient who is experiencing a gout flare and isconcomitantly receiving administration of clarithromycin orerythromycin, wherein concomitant administration of clarithromycin orerythromycin is administration within 1 to 2 days of orallyadministering the second colchicine dosage amount, and not repeatingcolchicine administration for at least three days.

In another embodiment, a method of using colchicine to treat a goutflare in an adult human gout patient so as to reduce the occurrence ofcolchicine toxicity when said patient is receiving concomitantadministration of clarithromycin or erythromycin comprises administeringa reduced colchicine dosage amount to the patient to treat gout flares,wherein the reduced colchicine dosage amount is about 50% to about 75%of a manufacturer's recommended colchicine dosage amount in the absenceof concomitant clarithromycin or erythromycin administration, and notrepeating colchicine administration for at least three days, whereinconcomitant administration of clarithromycin or erythromycin isadministration within 1 to 2 days of orally administering the secondcolchicine dosage amount.

In a one embodiment, the patient is administered the colchicineaccording to a colchicine dosing regimen of a single starting colchicinedose of no more than about 0.6 mg colchicine, followed by either noadditional colchicine doses within about 12, 24, 48, or 72 hours, orfollowed by at least one additional colchicine dose within 12 hours andno more frequently than once every hour (e.g., every 3, 4, 6, 8, or 12hours). In this embodiment, each additional colchicine dose is nogreater than about 0.3 mg and the patient may be an adult patient or apediatric patient. In one embodiment, the starting colchicine dose isabout 0.6 mg or about 0.3 mg, and each additional colchicine dose isabout 0.3 mg. When additional doses are administered, it is preferredthat only two, three, or four additional colchicine doses areadministered within about 24 hours. In another embodiment, the patientis an adult patient and the starting colchicine dose is about 0.6 mg andeach additional colchicine dose, if any, is about 0.3 mg. In oneembodiment only three additional colchicine doses are administeredwithin about 24 hours.

In another embodiment, colchicine is administered to a patient sufferingfrom a condition treatable with colchicine, and the concomitantmacrolide antibiotic is administered concurrently, or the patient hasrecently completed a dosing regimen of a macrolide antibiotic to treatan infection, and the patient is (immediately or within a period of twoweeks, preferably three days, more preferably within 48 hours or 24hours after completion of the macrolide antibiotic dosing regimen)administered a single dose of no more than about 0.6 mg of colchicine,preferably 0.3 mg or 0.6 mg of colchicine. For example, the startingcolchicine dose is about 0.6 mg and only one additional colchicine doseis administered within about 24 hours and the additional colchicine doseis about 0.6 mg.

A preferred antibiotic for use in the disclosed methods is one that isan inhibitor of either or both of CYP3A and P-glycoprotein, preferablyboth. In certain embodiments, the antibiotic is dirithromycin,erythromycin, roxithromycin, or more preferably, clarithromycin orerythromycin. The clarithromycin may be administered to the patient at adosage amount of about 500 mg daily and the colchicine dosing regimen isone about 0.6 mg colchicine dose to start, followed by 0, 1, 2, 3, or 4additional colchicine doses of about 0.6 mg every 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, or 12 hours (e.g., every 2, 3, 4, 5, or 6 hours) after thepreceding colchicine dose. Alternately, the clarithromycin may beadministered to the patient at a dosage amount of about 1000 mg dailyand the colchicine dosing regimen is one about 0.3 mg colchicine dose tostart, followed by 0, 1, 2, 3, or 4 additional colchicine doses of about0.3 mg each every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours (e.g.,every 3, 4, 5, or 6 hours) after the preceding colchicine dose. In apreferred regimen for treatment of acute gout flares, ingestion ofcolchicine is continued until a total of no more than about 1.2, 1.4,1.6, 1.8, 2, or 2.4 mg of colchicine has been ingested, after whichingestion of colchicine is stopped until a subsequent acute gout flareoccurs. In still another preferred regimen, clarithromycin may beadministered to a patient, e.g., at a dosage amount of about 250 mgB.I.D. for a period of about 7 to 10 days, and the colchicine dosingregimen is administered to the patient upon completion of theclarithromycin dosing regimen, wherein the colchicine dosing regimenconsists of the administration of no more than one dose of no more than0.6 mg of colchicine. In one embodiment, the colchicine is administeredas a dosage form of 0.6 mg (e.g., one 0.6 mg colchicine tablet), or 0.3mg (e.g., one half of a 0.6 mg tablet) of colchicine and administrationof the dosage form is not repeated within a period of at least about twodays, preferably at least about three days.

In these and other embodiments, the colchicine-responsive condition isgout (e.g. a gout flare in a chronic gout sufferer), familialMediterranean fever (FMF), thrombocytopenic purpura, pericarditis,scleroderma, or Behcet's disease. The gout may be an acute gout flare orchronic gout. For gout, the dosing regimen is generally continued untila total of no more than 2.4 mg of colchicine has been ingested, afterwhich ingestion of colchicine is stopped until a subsequent gout flareoccurs.

Another embodiment comprises administering colchicine to a patient alsotaking clarithromycin, or having completed treatment with clarithromycinwithin the prior 14 days, the patient being administered a single dosageamount of about 0.6 mg or about 0.3 mg of colchicine to treat a goutflare, which administration is not repeated within any 3-day period.

In another aspect, herein disclosed is a method for increasing the bloodplasma levels of colchicine in a patient to whom colchicine is beingadministered to treat or prevent a colchicine-responsive condition. Thismethod comprises the concomitant dosing of the patient with a sufficientamount of a macrolide antibiotic to increase the C_(max) of colchicineby about 167% to 200%, or to increase the AUC of colchicine in thepatient by about 240% to 250%, or to increase the plasma half-life ofcolchicine by about 233%, or to decrease the clearance of colchicine byabout 75%, compared to the C_(max), AUC, plasma half-life, or clearancein the same or a matched patient when not being administered aconcomitant macrolide antibiotic. In a one embodiment, the patient isbeing administered no more than three hourly doses of about 0.6 mg ofcolchicine or less, the macrolide antibiotic is clarithromycin, and theamount of macrolide antibiotic is from about 500 mg to about 1000 mg,with about 500 mg being preferred.

In another aspect, herein disclosed are methods for using colchicinewhich methods involve the use of pharmacy management systems.

In one aspect one such method comprises a pharmacy receiving aprescription for colchicine for a patient who is suffering from gout(e.g., acute gout flares or chronic gout) and who is concomitantly beingtreated with a macrolide antibiotic that is an inhibitor of CYP3A andP-glycoprotein, followed by the pharmacy dispensing colchicine inresponse to receipt of the prescription, wherein the dispensing ispreceded by entry into a first computer readable storage medium, infunctional communication with a computer, of a unique patient identifierfor said patient and at least one drug identifier for colchicine linkedto the patient identifier so as to indicate that colchicine is to beadministered to the patient. The computer is programmed to issue adrug-drug interaction alert when the at least one drug identifier forcolchicine is entered linked to the patient identifier so as to indicatethat colchicine is to be administered to the patient and when thepatient identifier is also linked to an identifier indicating that amacrolide antibiotic that is an inhibitor of CYP3A or P-glycoprotein isbeing concomitantly administered to the patient. Upon entry of the atleast one drug identifier for colchicine linked to the patientidentifier, a drug-drug interaction alert is issued to one or more of apharmacy technician, a pharmacist, or a pharmacy customer obtaining thecolchicine, said alert indicating that a macrolide antibiotic is beingconcomitantly administered to the patient and that prior to thecolchicine being dispensed, the colchicine dosing regimen must bereviewed and, if necessary adjusted, so that when the colchicine isdelivered to the pharmacy customer obtaining the colchicine it isdelivered along with instructions for the colchicine to be taken inaccordance with a dosing regimen of no more than one about 0.6 mgcolchicine dose to start (e.g., following the onset of the acute goutattack or the first sign of a gout flare) followed by either: noadditional colchicine doses within about 12, 24, 48, or 72 hours, or atleast one additional colchicine dose within about 12 hours and no morefrequently than once every hour and wherein each additional colchicinedose is no greater than about 0.6 mg, and wherein the patient ingeststhe colchicine as instructed.

The drug-drug interaction alert may be issued as one or both of awritten warning on a display screen of the pharmacy management computersystem, and a printed warning. The printed warning may be attached to orpackaged with the dispensed prescription.

In one aspect, the identifier indicating that a macrolide antibiotic isbeing concomitantly administered to the patient is an identifierindicating that the macrolide antibiotic is clarithromycin and is linkedto at least one further identifier indicating that the clarithromycin isprescribed so that 500 mg of clarithromycin is to be ingested by thepatient daily, in which case the dosing regimen for colchicine ispreferably one about 0.6 mg colchicine dose to start, optionallyfollowed by additional colchicine doses, e.g., 0, 1, 2, 3, or 4additional colchicine doses within 24 hours of about 0.3 mg ingestedevery 1, 2, 3, 4, 5, 6, 7, 8, 9 10, 11, or 12 hours (e.g., every 2, 3,4, 5, or 6 hours) after the preceding colchicine dose. In anotherembodiment, the identifier indicating that a macrolide antibiotic isbeing concomitantly administered to the patient is an identifierindicating that the macrolide antibiotic is clarithromycin is linked toat least one further identifier, entered into a second computer readablestorage medium in functional communication with a computer, the secondstorage medium being the same as or different from the first storagemedium, and the further identifier indicating that the clarithromycin isprescribed so that about 500 mg of clarithromycin is to be ingested bythe patient daily, in which case the colchicine dosing regimen is(preferably) one about 0.6 mg colchicine dose to start, followed by anabout 0.3 mg colchicine dose ingested every 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, or 12 hours (e.g., every six to eight hours) after the precedingcolchicine dose.

In yet another aspect, the identifier indicating that a macrolideantibiotic is being concomitantly administered to the patient is anidentifier indicating that the macrolide antibiotic is clarithromycinand is linked to at least one further identifier, entered into a secondcomputer readable storage medium in functional communication with acomputer, the second storage medium being the same as or different fromthe first storage medium, and the further identifier indicating that theclarithromycin is prescribed so that about 1000 mg of clarithromycin isto be ingested by the patient daily and the dosing regimen is one about0.3 mg colchicine dose to start, followed by an about 0.3 mg colchicinedose ingested every 2, 3, 4, 5, 6, 7, or 8 hours (e.g., every eight totwelve hours) after the preceding colchicine dose.

One dosing regimen calls for ingestion of colchicine to be continueduntil a total of no more than 1.2 mg or 2.4 mg of colchicine has beeningested, after which ingestion of colchicine is to be stopped, e.g.,for at least 2, 3, 4, 5, 6, or 7 days, or until a subsequent acute goutflare, or the first sign of a subsequent gout flare, occurs.

Also disclosed herein is a dosage amount adjustment method foradministering colchicine to a patient to treat a medical condition, thepatient concomitantly suffering from an infection amenable to treatmentwith a macrolide antibiotic. The method comprises determining a first, asecond, and a subsequent monotherapy colchicine dosage amount and acolchicine treatment schedule; and determining an antibiotic dosageamount and an antibiotic treatment schedule; and administering themacrolide antibiotic to the patient at the antibiotic dosage amountaccording to the antibiotic treatment schedule while concomitantlyadministering colchicine to the patient according to the colchicinetreatment schedule at a first, a second, and a subsequent polytherapycolchicine dosage amount, each of which is a fraction of each of thecorresponding first, second, and subsequent monotherapy colchicinedosage amounts, the fraction being less than or equal to about ⅔.

An alternate embodiment of this method comprises determining amonotherapy colchicine dosage amount and a colchicine treatmentschedule, each adapted so that, when colchicine is administered to thepatient in the absence of concomitant administration of the antibioticat the monotherapy colchicine dosage amount according to the colchicinetreatment schedule, a therapeutic circulating plasma level of colchicineis predicted to be achieved in the patient that is safe and effective totreat the condition in the patient while posing an acceptable adverseeffect risk; and determining an antibiotic dose and an antibiotictreatment schedule, each adapted so that, when the antibiotic isadministered to the patient at the antibiotic dosage amount according tothe antibiotic treatment schedule, a circulating level of the antibioticis predicted to be achieved in the patient that is safe andtherapeutically effective to treat the infection in the patient andadministering the antibiotic to the patient at the antibiotic dosageamount according to the antibiotic treatment schedule whileconcomitantly administering colchicine to the patient at a polytherapycolchicine dosage amount that is a fraction less than or equal to ½ ofthe monotherapy colchicine dosage amount to the patient according to thecolchicine treatment schedule.

According to this embodiment, upon the administering of the antibioticto the patient at the antibiotic dosage amount according to theantibiotic treatment schedule while concomitantly administeringcolchicine to the patient at the polytherapy colchicine dose accordingto the colchicine treatment schedule, the therapeutic circulating levelof colchicine is achieved in the patient. Preferably, the fraction isselected from 1/12, ⅙, ¼, ⅓, 5/12, and ½, more preferably, the fractionis ⅓ or ½. Preferably the antibiotic is selected from clarithromycin,dirithromycin, erythromycin and roxithromycin. Exemplary conditions areselected from gout, FMF, thrombocytopenic purpura, and Behçet's disease.In a preferred embodiment, the gout is an acute gout flare and thecolchicine treatment schedule is an acute treatment schedule adapted fortreatment of acute gout flares, or the gout is chronic gout, and thecolchicine treatment schedule is a chronic treatment schedule adaptedfor prophylaxis of flares. In another embodiment, the fraction is ⅓ or ½and treatment with colchicine is initiated subsequent to initiation oftreatment with clarithromycin.

In one embodiment, each of the monotherapy colchicine doses and thecolchicine treatment schedule are each adapted so that, when colchicineis administered to the patient at the monotherapy colchicine doseaccording to the colchicine treatment schedule in the absence ofconcomitant administration of the antibiotic, a therapeutic circulatinglevel of colchicine is predicted to be achieved in the patient that ispredicted to be safe and effective to treat the condition in the patientwhile posing an acceptable adverse effect risk.

Alternately, the antibiotic dose and the antibiotic treatment scheduleare each adapted so that, when the antibiotic is administered to thepatient at the antibiotic dose according to the antibiotic treatmentschedule a circulating level of the antibiotic is predicted to beachieved in the patient that is therapeutically effective to treat theinfection in the patient.

In one embodiment, upon the administration of the antibiotic to thepatient at the antibiotic dose according to the antibiotic treatmentschedule while concomitantly administering colchicine to the patientaccording to the colchicine treatment schedule at the polytherapycolchicine dose, a therapeutic circulating level of colchicine ispredicted to be achieved in the patient that is predicted to be safe andeffective to treat the condition in the patient while posing anacceptable adverse effect risk. In one embodiment, each subsequentcolchicine dose is the same as the second colchicine dose. In anotherembodiment, each of the second and subsequent colchicine doses are thesame as the first colchicine dosage amounts. In another, the fraction isselected from about 1/12, about ⅙, about ¼, about ⅓, about 5/12, about½, and about 7/12, e.g., about ½ or about ⅔. In certain embodiments, thecolchicine treatment schedule is once-a-day, twice-a-day,three-times-a-day or four-times-a-day.

Acute Gout

Acute gout, or gout flares, can be treated according to the followingtreatment schedule. This table indicates the original, or intended,dosage amount, i.e., the dosage amount of colchicine recommended absentconcomitant administration of the drugs listed below. This table alsopresents the dosage amount adjustment, or the recommended colchicinedosage amount to be administered when strong and moderate CYP3A4 andP-gp inhibitors are administered concomitantly with colchicine when thepatient is being treated for a gout flare.

Colchicine Dose Recommendation Original Intended Drug Dose (Total Dose)Dose Adjustment Strong CYP3A4 Regimen Reduced by Two Thirds InhibitorsClarithromycin 1.2 mg (2 tablets) at 0.6 mg (1 tablet) × the first signof the 1 dose. Dose to be flare followed by 0.6 repeated no earlier mg(1 tablet) one hour than 3 days. later. Erythromycin Dose to be repeatedno earlier than 3 days.Chronic Gout

For chronic gout (prophylaxis of gout flares), an original intendeddaily dosage amount is 1.2 mg or 6 mg. Alternatively, an intended dailydosage amount of chronic gout can be as much as 2.4 mg per day. Thedaily dosage amount for chronic gout can be administered at one time ordosed at intervals throughout the day, e.g. twice daily, three timesdaily, or four times daily.

Chronic gout, with and without a concomitant dose of another drug, canbe treated according to the following treatment schedule:

Colchicine Dose Adjustment for Co-administration with Interacting Drugsif No Alternative Available

Colchicine Dose Recommendation Drug Original Intended Dose DoseAdjustment Clarithromycin 0.6 mg twice daily 0.3 mg once daily 0.6 mgonce daily 0.3 mg once every other day Erythromycin 0.6 mg twice daily0.3 mg once daily 0.6 mg once daily 0.3 mg once every other day

The dosage amount of 0.3 mg once every other day is administered eitheras 0.3 mg once every other day or 0.15 mg once a day.

Familial Mediterranean Fever

Familial Mediterranean Fever (FMF) can be treated according to thefollowing intended daily dosing schedule:

Daily dosage amount Age Usual Maximum Adults and children >12 years 1.2mg 2.4 mg Children >6 to 12 years 0.9 mg 1.8 mg Children 4 to 6 years0.3 mg 1.8 mg

When colchicine is given to patients with FMF concomitantly with otherdrugs, the adjusted (reduced) dosage amount of colchicine, according tothis embodiment, is provided in the table below:

Concomitant Drug Noted or Anticipated Class or Food Outcome ClinicalComment Strong CYP3A4 Significant increase in Use colchicine withInhibitors: colchicine plasma caution at reduced clarithromycin levels¹;fatal maximum dose of 0.3 mg colchicine toxicity has twice daily withincreased been reported with monitoring for adverse clarithromycin, aeffects. In patients with strong CYP3A4 renal or hepatic inhibitor.Similarly, impairment, use of significant increase colchicine inconjunction in colchicine plasma with these drugs is levels isanticipated contraindicated. with other strong CYP3A4 inhibitors.Moderate CYP3A4 Significant increase in Use colchicine with inhibitors:colchicine plasma caution at reduced erythromycin concentration ismaximum dose of 0.6 mg anticipated. twice daily with increasedNeuromuscular monitoring for adverse toxicity has been effects. Inpatients with reported with renal or hepatic diltiazem and impairment,use a verapamil maximum dose of 0.3 mg interactions. twice daily.

Colchicine is one of the most widely used drugs for treating familialMediterranean fever (FMF). It has been reported that 5-10% of FMFpatients do not show a beneficial response to colchicine administration.A polymorphism in the ABCB1 gene, the “ABCB1 3435 C to T polymorphism”has been reported to correlate with this lack of response to colchicinetreatment, with patients with the homozygous TT genotype exhibiting themost pronounced “non-responder” phenotypes.

Accordingly, in another aspect, provided herein is a method for treatinga patient suffering from FMF, which patient is a colchicinenon-responder. In one embodiment, the patient is homozygous for the TTgenotype of the ABCB1 3435 C to T polymorphism. The method entails theconcomitant administration of a Pgp inhibitor and colchicine to thepatient. A preferred Pgp inhibitor for use in this method is verapamilor cyclosporine-A, more preferably a macrolide antibiotic, preferablydirithromycin, erythromycin or roxithromycin, or, more preferablyclarithromycin. Dosage amounts of the Pgp inhibitor for this purposecorrespond to those called for in the prescribing information for thedrug in question. For clarithromycin, the dosage amounts are 500 to 1000mg per day and duration of clarithromycin dosing is preferably one, two,or three days, repeated weekly or bi-weekly. Preferred colchicine dosingregimens for this purpose are the same as used for treatment of FMF inresponders, though the doses of colchicine administered may be increasedas tolerated, e.g., up to two to three times the typical doses.

These and other embodiments, advantages and features of the presentinvention are further elaborated herein below.

DETAILED DESCRIPTION

Following multiple oral doses (0.6 mg twice daily), the mean eliminationhalf-life of colchicine in young healthy volunteers (mean age 25 to 28years of age) is 26.6 to 31.2 hours.

Pharmacy management systems are computer-based systems that are widelyused by commercial pharmacies to manage prescriptions and to providepharmacy and medical personnel with warnings and guidance regardingdrugs being administered to patients. Such systems typically providealerts warning either or both of health care providers and patients whena drug that may be harmful to the particular patient is prescribed. Forexample, such systems can provide alerts warning that a patient has anallergy to a prescribed drug, or is receiving concomitant administrationof a drug that can have a dangerous interaction with a prescribed drug.U.S. Pat. Nos. 5,758,095, 5,833,599, 5,845,255, 6,014,631, 6,067,524,6,112,182, 6,317,719, 6,356,873, and 7,072,840, each of which isincorporated herein by reference, disclose various pharmacy managementsystems and aspects thereof. Many pharmacy management systems are nowcommercially available, e.g., CENTRICITY Pharmacy from BDM InformationSystems Ltd., General Electric Healthcare, Waukesha, Wis., Rx30 PharmacySystems from Transaction Data Systems, Inc., Ocoee, Fla., SPEED SCRIPTfrom Digital Simplistics, Inc., Lenexa, Kans., and various pharmacymanagement systems from OPUS-ISM, Hauppauge, N.Y.

In the specification and claims that follow, references will be made toa number of terms which shall be defined to have the following meaning.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterm “or” means “and/or”. The terms “comprising”, “having”, “including”,and “containing” are to be construed as open-ended terms (i.e., meaning“including, but not limited to”).

“Concomitant” and “concomitantly” as used herein refer to theadministration of at least two drugs to a patient either simultaneouslyor within a time period during which the effects of the firstadministered drug are still operative in the patient. Thus, if the firstdrug is, e.g., clarithromycin and the second drug is colchicine, theconcomitant administration of the second drug can occur as much as oneto two weeks, preferably within one to seven days, after theadministration of the first drug. This is because clarithromycin canexert a long-lasting inhibition of CYP3A isozymes so that CYP3A activityin the patient may not return to pre-clarithromycin-administrationlevels for as much as two weeks after the cessation of clarithromycinadministration. If colchicine is the first drug, administration of asecond drug would be concomitant if done within 1 to 2 days, preferably12 to 24 hours.

“Dosage amount” means an amount of a drug suitable to be taken during afixed period, usually during one day (i.e., daily).

“Dosage amount adapted for oral administration” means a dosage amountthat is of an amount deemed safe and effective for the particularpatient under the conditions specified. As used herein and in theclaims, this dosage amount is determined by following therecommendations of the drug manufacturer's Prescribing Information asapproved by the US Food and Drug Administration.

“Dosing regimen” means the dose of a drug taken at a first time by apatient and the interval (time or symptomatic) and dosage amounts atwhich any subsequent doses of the drug are taken by the patient. Eachdose may be of the same or a different dosage amount.

A “dose” means the measured quantity of a drug to be taken at one timeby a patient.

A “patient” means a human or non-human animal in need of medicaltreatment. Medical treatment can include treatment of an existingcondition, such as a disease or disorder, prophylactic or preventativetreatment, or diagnostic treatment. In preferred embodiments the patientis human.

“Providing” means giving, administering, selling, distributing,transferring (for profit or not), manufacturing, compounding, ordispensing.

“Risk” means the probability or chance of adverse reaction, injury, orother undesirable outcome arising from a medical treatment. An“acceptable risk” means a measure of the risk of harm, injury, ordisease arising from a medical treatment that will be tolerated by anindividual or group. Whether a risk is “acceptable” will depend upon theadvantages that the individual or group perceives to be obtainable inreturn for taking the risk, whether they accept whatever scientific andother advice is offered about the magnitude of the risk, and numerousother factors, both political and social. An “acceptable risk” of anadverse reaction means that an individual or a group in society iswilling to take or be subjected to the risk that the adverse reactionmight occur since the adverse reaction is one whose probability ofoccurrence is small, or whose consequences are so slight, or thebenefits (perceived or real) of the active agent are so great. An“unacceptable risk” of an adverse reaction means that an individual or agroup in society is unwilling to take or be subjected to the risk thatthe adverse reaction might occur upon weighing the probability ofoccurrence of the adverse reaction, the consequences of the adversereaction, and the benefits (perceived or real) of the active agent. “Atrisk” means in a state or condition marked by a high level of risk orsusceptibility.

Pharmacokinetic parameters referred to herein describe the in vivocharacteristics of drug (or a metabolite or a surrogate marker for thedrug) over time. These include plasma concentration (C), as well asC_(max), C_(n), C₂₄, T_(max), and AUC. “C_(max)” is the measured plasmaconcentration of the active agent at the point of maximum, or peak,concentration. “C_(min)” is the measured plasma concentration of theactive agent at the point of minimum concentration. “C_(n)” is themeasured plasma concentration of the active agent at about n hours afteradministration. “C₂₄” is the measured plasma concentration of the activeagent at about 24 hours after administration. The term “T_(max)” refersto the time from drug administration until C_(max) is reached. “AUC” isthe area under the curve of a graph of the measured plasma concentrationof an active agent vs. time, measured from one time point to anothertime point. For example AUC_(0-t) is the area under the curve of plasmaconcentration versus time from time 0 to time t, where time 0 is thetime of initial administration of the drug. Time t can be the last timepoint with measurable plasma concentration for an individualformulation. The AUC_(0-∞) or AUC_(0-INF) is the calculated area underthe curve of plasma concentration versus time from time 0 to timeinfinity. In steady-state studies, AUC_(0-τ) is the area under the curveof plasma concentration over the dosing interval (i.e., from time 0 totime τ (tau), where tau is the length of the dosing interval. Otherpharmacokinetic parameters are the parameter K_(e) or K_(el), theterminal elimination rate constant calculated from a semi-log plot ofthe plasma concentration versus time curve; t_(1/2) the terminalelimination half-life, calculated as 0.693/K_(el). CL/F denotes theapparent total body clearance after administration, calculated as TotalDose/Total AUC_(∞); and V_(area)/F denotes the apparent total volume ofdistribution after administration, calculated as Total Dose/(TotalAUC_(∞)×K_(el)).

“Side effect” means a secondary effect resulting from taking a drug. Thesecondary effect can be a negative (unfavorable) effect (i.e., anadverse side effect) or a positive (favorable) effect.

The most frequently reported adverse side effects to colchicine therapyare gastrointestinal, specifically abdominal pain with cramps, diarrhea,nausea, and vomiting. Less frequently or rarely reported adverse sideeffects associated with colchicine therapy include anorexia,agranulocytosis, allergic dermatitis, allergic reactions, alopecia,angioedema, aplastic anemia, bone marrow depression, myopathy,neuropathy, skin rash, thrombocytopenic disorder, and urticaria.

Whether a patient experiences an adverse side effect can be determinedby obtaining information from the patient regarding onset of certainsymptoms which may be indicative of the adverse side effect, results ofdiagnostic tests indicative of the adverse side effect, and the like.

The following examples further illustrate aspects of this disclosure butshould not be construed as in any way limiting its scope. In particular,the conditions are merely exemplary and can be readily varied by one ofordinary skill in the art.

EXAMPLES Example 1 Pharmacokinetic Study in Healthy Adults of Single Vs.Multiple Oral Doses of Colchicine Tablets

This study was a single-center, open-label, single-sequence, two-periodstudy to evaluate the pharmacokinetic profile of colchicine followingsingle and multiple oral doses of colchicine tablets, 0.6 mg, in healthyvolunteers.

In Period 1, study subjects received a 0.6-mg dose of colchicine afteran overnight fast of at least 10 hours. In Period 2, subjects received a0.6-mg dose of colchicine in the morning and the evening (approximately12 hours later) for 10 days (steady state regimen). Subjects received alight breakfast served 60 minutes following dose administration in themorning and the evening dose was administered 90 minutes after anevening meal on Days 15 through 24 only. On Day 25, the colchicine dosewas administered after an overnight fast of at least 10 hours and lunchwas served 4 hours post-dose. Study periods were separated by a 14-daywashout. Following the single dose and the last dose of the multipledose regimen (beginning on the mornings of Day 1 and Day 25,respectively), blood samples were collected (6 mL each) from eachsubject within 1 hour prior to dosing and after dose administration atstudy hours 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 (while confined)and 36, 48, 72, and 96 (on an outpatient basis). Plasma concentrationsof colchicine and its metabolites were determined using validatedLC/MS-MS methods.

Thirteen healthy, non-smoking subjects with a mean age of 25.5 years(range 19 to 38 years) and within 15% of ideal body weight were enrolledin this study. All subjects completed both dosing periods according toprotocol.

After a single dose, plasma concentrations are no longer quantifiable 24hours post-dose in all but 1 subject. After the last dose of the steadystate regimen, concentrations remained quantifiable for 48 to 72 hours.Review of individual subject data shows that no subject experienced asecondary colchicine peak, either following a single dose or uponmultiple dosing.

All 2-O-demethylcolchicine (2-DMC) concentrations were below the levelof quantitation (LOQ, 0.2 ng/mL) and only one sample from 1 subject (of13 subjects) had a detectable 3-O-demethylcolchciine (3-DMC)concentration, which was near the level of quantitation. Therefore,metabolites are not discussed further.

In healthy adults, colchicine appears to be readily absorbed when givenorally, reaching a mean maximum plasma concentration of 2.5 ng/mL in 1.5hours after a single dose. The drug is distributed widely, with anapparent volume of distribution of 540 L, greatly exceeding total bodywater. The elimination half-life as calculated following a single oraldose is approximately 5 hours. Levels were not detectable by 24 hourspost-dose and this is therefore not an accurate estimate.Pharmacokinetic parameter values are summarized in the table below.

Review of trough plasma concentrations indicates that steady state wasattained by approximately the eighth day of dosing for most subjects.Colchicine may have a diurnal variation reflected in the observed Cminconcentrations at steady state. Cmin concentrations prior to the morningdose are approximately 12% higher than the Cmin concentrations prior tothe evening dose (Day 23 and Day 24). The mean Cmin concentrationobserved on Day 25 was 0.907 ng/mL.

Colchicine accumulated following administration of multiple doses to anextent greater than expected. Exposure was nearly two-fold higher(approximately 1.7 based on AUC [Day 25 AUC_(0-τ)/Day 1 AUG_(0-∞)] andapproximately 1.5 based on Cmax [Day 25 C_(max)/Day 1 C_(max)]). Thisobservation could be attributable to an underestimation of AUG∞following a single dose. With the higher plasma levels that occur withrepeated dosing, a longer terminal elimination half life is apparent,26.6 hours. Pharmacokinetic parameter values are summarized in thetables below.

TABLE 1 Colchicine Pharmacokinetic Parameter Values FollowingAdministration of A Single Oral Dose of Colchicine 0.6 mg in HealthyAdults (N = 13) AUC_(0-t) AUC_(0-inf) C_(max) T_(max) K_(el) T_(1/2)(pg-hr/mL) (pg-hr/mL) (pg/mL) (hr) (1/hr) (hr) MEAN 10508.54 12281.902470.77 1.50 0.1829 4.95 STDEV 3544.82 4423.34 706.98 0.54 0.0592 4.43 %CV 33.73 36.02 28.61 36.00 32.39 89.54 MEDIAN 10560.90 11451.45 2714.001.50 0.1992 3.48 MIN 4812.88 7252.66 1584.00 1.00 0.0359 2.84 MAX18128.65 23838.48 3977.00 3.00 0.2443 19.29

TABLE 2 Colchicine Pharmacokinetic Parameter Values FollowingAdministration of Multiple (b.i.d.) Oral Doses of Colchicine 0.6 mg inHealthy Adults (N = 13) AUC_(0-t) AUC_(0-τ) AUC_(0-inf) C_(max) C_(min)C_(ave) T_(max) K_(el) T_(1/2) (pg-hr/mL) (pg-hr/mL) (pg-hr/mL) (pg/mL)(pg/mL) (pg/mL) (hr) (1/hr) (hr) MEAN 43576.96 29056.23 54198.77 3553.15906.51 1210.68 1.31 0.03 26.60 STDEV 9333.26 4531.30 9214.54 843.45152.19 188.80 0.60 0.00 4.33 % CV 21.42 15.59 17.00 23.74 16.79 15.5945.61 16.34 16.26 MEDIAN 41925.10 28452.15 54113.43 3734.00 903.501185.51 1.00 0.03 26.51 MIN 29328.78 20791.98 37599.76 1977.00 636.23866.33 0.50 0.02 20.82 MAX 58265.35 36083.95 67944.65 4957.00 1149.671503.50 3.00 0.03 33.65

TABLE 3 Mean (% CV) Colchicine Pharmacokinetic Parameter ValuesFollowing Administration of Single and Multiple (b.i.d.) Oral Doses ofColchicine 0.6 mg in Healthy Adults Vd/F (L) CL/F (L/hr) Colchicine 0.6mg Single Dose (N = 13) Day 1 540.5 (31.0)   341.5 (54.4) Colchicine 0.6mg b.i.d. × 10 days Day 25 1150 (18.73)  30.3 (19.0) CL = Dose/AUC_(0-t)(Calculated from mean values) Vd = CL/Ke (Calculated from mean values)

In the above table, the parameter CL/F denotes the apparent total bodyclearance after administration, calculated as Total Dose/TotalAUC0-_(tau); and V_(d)/F denotes the apparent total volume ofdistribution after administration, calculated as Total Dose/(TotalAUC_(∞)×K_(el)).

Example 2 Clinical Drug-Drug Interaction Study of Colchicine andClarithromycin

A single-center, open-label, one sequence, two-period study was carriedout in 23 healthy subjects. On Day 1, a single 0.6-mg dose of colchicinewas administered. After completing a 21-day washout period, all subjectsreceived 250 mg of clarithromycin administered twice daily for 7 days(Days 22 through 29), a sufficient dose and duration to inhibit CYP3A4and Pgp. On the final day (Day 29), a single dose of colchicine wasco-administered with the clarithromycin dose.

When combined with steady-state clarithromycin, there is a significantincrease in exposure to colchicine as compared to when colchicine isgiven alone: the mean C_(max) and AUC_(0-τ) concentrations increased167% and 250%, respectively. In addition, co-administration ofclarithromycin and colchicine resulted in an increase of 233% in theplasma elimination half-life (t½) of colchicine and a 75% decrease inapparent clearance (CL/F). A summary of the mean (% CV) colchicinepharmacokinetic parameters for Day 1 (colchicine administered alone) andDay 29 (colchicine co-administered with steady-state clarithromycin) aregiven in the table below and illustrated in the table that follows.

TABLE 4 Comparison of Single-Dose Colchicine (0.6 mg, Alone) andSingle-Dose Colchicine (0.6 mg) Co-Administered with Steady-StateClarithromycin in Healthy Adults C_(max) T_(max) ¹ AUC_(0-t) AUC_(∞) KeVd/F CL/F t_(1/2) DAY (ng/mL) (h) (ng · h/mL) (ng · h/mL) (h⁻¹) (L)(L/hr) (h) Colchicine Alone (n = 23) 1 3 1.00 12 16 0.132 432 46.8 9(30.97) (0.5-2.0) (37.6) (49.6) (46.87) (56.1) (43.7) (126.4)Colchicine + Clarithromycin (n = 23) 29 8 1.0  42 53 0.0298 493 12 30(23.74) (1.0-5.0) (23.3) (22.8) (90.82) (33.69) (23.8) (41.37) p value<0.0001   0.05061 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.0001¹T_(max) mean (range)

Recitation of ranges of values herein are merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range, unless otherwise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein. The endpoints of all ranges directed to thesame component or property are inclusive and independently combinable.

All methods described herein can be performed in a suitable order unlessotherwise indicated or clearly contradicted by context. The use of anyand all examples, or exemplary language (e.g., “such as”) herein isintended to better illuminate the disclosure and is non-limiting unlessotherwise specified. No language in the specification should beconstrued as indicating that any non-claimed element as essential to thepractice of the claimed embodiments. Unless defined otherwise, technicaland scientific terms used herein have the same meaning as is commonlyunderstood by one of skill in the art to which this disclosure belongs.The terms wt %, weight percent, percent by weight, etc. are equivalentand interchangeable

Embodiments are described herein, including the best modes known to theinventors. Variations of such embodiments will become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theskilled artisan is expected to employ such variations as appropriate,and the disclosed methods are expected to be practiced otherwise than asspecifically described herein. Accordingly, all modifications andequivalents of the subject matter recited in the claims appended heretoare included to the extent permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is encompassed unless otherwise indicated herein or otherwiseclearly contradicted by context.

1. A method of using colchicine for prophylactic treatment of goutflares in an adult human gout patient so as to reduce the occurrence ofcolchicine toxicity when said patient is receiving concomitantadministration of clarithromycin, said method comprising: orallyadministering a reduced colchicine daily dosage amount to the patientfor prophylactic treatment of gout flares, wherein the reducedcolchicine daily dosage amount is a 75% reduction of a colchicine dosageamount adapted for oral administration to the gout patient for theprophylaxis of gout flares in the absence of concomitant administrationof clarithromycin, wherein concomitant administration of clarithromycinis administration within 1 to 2 days of orally administering the secondcolchicine dosage amount.
 2. The method of claim 1, wherein thecolchicine dosage amount adapted for oral administration to the goutpatient for the prophylaxis of gout flares in the absence of concomitantadministration of clarithromycin is 0.6 mg twice per day.
 3. The methodof claim 2, wherein the reduced colchicine dosage amount is 0.3 mg onceper day.
 4. The method of claim 1, wherein the colchicine dosage amountadapted for oral administration to the gout patient for the prophylaxisof gout flares in the absence of concomitant administration ofclarithromycin is 0.6 mg once per day.
 5. The method of claim 4, whereinthe reduced colchicine dosage amount is 0.3 mg once every other day.